Colon cancer is one of the most familial of all cancers with present investigations suggesting that as many as 35% of cases arise on the basis of inherited factors. The known syndromes of colon cancer, however, account for only a small fraction of cases, probably less than 5%. The genetic etiology, precise phenotype, and the optimal clinical screening and management of the remainder of inherited cases remain elusive. We will apply two aims to find new susceptibility genes: 1) large high-risk kindreds with multiple cases of colon cancer and adenomatous polyps, but no known colon cancer syndrome, will be recruited from Utah.s unique genealogic database resources and from referrals for genome-wide linkage analysis and; 2) three large, well characterized kindreds with the highly variable attenuated form of familial adenomatous polyposis, will be investigated for genes that modify APC phenotypic expression using nonparametric multivariate linkage analysis. Our third aim is to clinically characterize the high-risk and AFAP families to: 1) precisely define the phenotype for linkage analysis; 2) allow clarification of the penetrance and phenotype of each disease gene and mutation once these are identified; 3) define proper surveillance and clinical care for cancer prevention in these settings. The high-risk kindred members selected for study will be examined by colonoscopy to characterize the polyp phenotype in addition to the known cancer phenotype and these results will be used for linkage studies to identify cancer susceptibility loci. Additional members of the AFAP kindreds, who are now over age 18 since previous family recruitment in 1996 will be genotyped for the family mutation, be examined by colonoscopy and included in linkage analysis for genetic modifiers. Multivariate analysis of the AAPC kindreds will include polyp number as a quantitative trait, with adjustments made for age, sex, and epidemiologic exposures.